The present invention is directed to novel pyrrolopyrimidine compounds, their salts, and compositions comprising them. In particular, the present invention is directed to novel aryl-amino substituted pyrrolopyrimidine compounds that inhibit the activity of at least two of the Abl, Aurora-A, Blk, c-Raf, cSRC, Src, PRK2, FGFR3, Flt3, Lck, Mek1, PDK-1, GSK3β, EGFR, p70S6K, BMX, SGK, CaMKII, Tie-2, Ret, IGF-1R, Ron, and KDR kinases in animals, including humans, for the treatment and/or prevention of various diseases and conditions such as cancer.
Cells may migrate and divide inappropriately if the signals for division or motility cannot be stopped. This might occur if the complex system of control proteins and messengers, which signal changes in the actin system, goes awry. One such control factor is the proto-oncogene protein Ab1, a tyrosine kinase. It is implicated in cancer, including leukemia. Accordingly, it is desirable to identify inhibitors of Ab1.
The Aurora kinase family is one regulator of chromosome segregation—regulating the structure and function of centrosomes and mitotic spindle. One member, the Aurora-A kinase, has been shown to play a role in tumorigenesis—being located at a chromosomal hot-spot, 20q13, frequently amplified in a variety of human cancers such as those of colon, ovary, breast and pancreas. It appears that overexpression of Aurora-A kinase alone is sufficient to cause aneupoidy in normal diploid epithelial cells. Over-expression of Aurora-A kinase in NIH3T3 cells results in centrosome aneupoidy. Thus, it is desirable to identify inhibitors of Aurora-A.
Shortly after birth, mice expressing an activated, mutant form of Blk form massive, monoclonal lymphomas and die. (S. V. Desiderio ath. Hughs Medical Institute). Thus, it is likely that Blk regulates cell proliferation. Further, experiments with Blk antisense appear to implicate Blk kinase with growth inhibition and apoptosis. (X. Yao and D. W. Scott, Proc. Nat. Acad. Sci., 90:7946-7950 (1993)). Thus, it is desirable to identify inhibitors of Blk.
C-Raf is an extracellular signal-regulated kinase and a downstream effector of Ras. It functions to suppress apoptosis and regulates cell differentiation. Thus, over-expression can lead to unwarranted suppression of apoptosis and unchecked cell differentiation. Thus, it is desirable to identify inhibitors of c-Raf.
The cytoplasmic tyrosine kinase cSRC, or c-Src, is involved in the signal transduction pathway and is elevated in breast cancer cell lines. Similarly, Src is involved in the regulation of cell growth and transformation. Thus over-expression of Src or cSRC can lead to excess proliferation. Thus, it is desirable to identify inhibitors of Src or c-SRC.
The Protein Kinase c-Related Kinase 2, or PRK2, mediates cytoskeletal organization. It has been implicated in promoting the PDK1-dependent activation of Akt, thereby regulating cell-cycle progression, cell growth, cell survival, cell motility and adhesion, translation of mRNA into protein, and angiogenesis. Thus, it is desirable to identify inhibitors of PRK2.
FGFR3 and Tie-2 are receptor tyrosine kinases that are believed to be important mediators of tumor angiogenesis. For example, FGFR3 mutations are often seen in bladder cancer cells. Tie-2 is a protein receptor found on cells lining blood vessels. When activated by growth factors secreted by tumor cells, Tie2 triggers vessel cell walls to part and grow new capillaries. Thus, it is desirable to identify inhibitors of FGFR3 or Tie-2. Flt3, also known as “vascular endothelial cell growth factor receptor 3” or VEGFR-3, is believed to assist in vascular development important to angiogenesis. Thus, it is desirable to identify inhibitors of Flt3.
Lck, along with fyn, is an Src kinase implicated in cancer, including breast and colon cancer. Accordingly, it is desirable to identify inhibitors of Lck.
Mek1 is a kinase in the Ras pathway strongly implicated in many cancers, including breast, colon, and ovarian cancer. Thus, it is desirable to identify inhibitors of Mek1.
PDK-1 is a kinase that activates the PI3K/PKB signalling pathway, which is often uncoupled and separate from the EGFR pathway. In particular, a PDK-1 phosphorylating step is essential to activation of PKB (D. R. Alessi et al., Curr. Biol., 7:261-269 (1997)). Additionally, PDK-1 activates other oncogene kinases such as PKA, ribosomal p90 S6 kinase (RSK), p70 S6 kinase (S6K), serum and glucocorticoid activated kinase (SGK), PKC-related kinase-2 (PRK-2) and MSK-1 (R. M. Biondi et al., Biochem. J., 372:1-13 (2003)). Thus, inhibition of PDK-1 can be multiply effective in treatment of cancer and tumors, including glioblastoma, melanoma, prostate, endometrial carcinoma, breast, ovarian, and non-small cell lung cancer (NSCLC), because PDK-1 regulates several oncogenic pathways. Accordingly, it is desirable to identify compounds that inhibit PDK-1.
GSK3β kinase is believed to play a strong part in cancers such as breast, ovarian, pancreatic, and prostate cancer. Thus, it is desirable to identify compounds that inhibit GSK3β.
Cell division involves signalling pathways from the cell exterior and interior. Signals travel the pathways and regulate the various activities of cell cycle control genes. Cancer cells have mis-regulation of such signal pathways and control genes—thereby leading to inappropriate or uncontrolled cell division. Over-expression of oncogenes (proteins that signal cells to proliferate) is one such mis-regulation. The Epidermal Growth Factor Receptor (EGFR) is one such oncogene, which is over-expressed in cancers such as brain, breast, gastrointestinal, lung, ovary and prostate cancers. There are selective EGFR inhibitors being investigated for use against cancer. For example, the 4-anilinoquinazoline compound Tarceva® inhibits only EGFR kinase with high potency, although it can inhibit the signal transduction of other receptor kinases that probably heterodimerize with the EGFR. Nevertheless, other compounds that inhibit EGFR remain needed.
The serine-threonine kinase p70S6K is at the end of one pathway that controls cell growth and is frequently activated in many tumors, including uterine, adenocarcinoma, myeloma, and prostate cancers. Thus, it is desirable to identify compounds that inhibit p70S6K.
BMX is a tyrosine kinase involved in interleukin-6 induced differentiation of prostate cancer cells. It plays a role in EGF-induced apoptosis of breast cancer cells, and is expressed in granocytes and myoloid leukemias, as well as other cancers. Thus, it is desirable to identify compounds that inhibit BMX.
The serum and glucocorticoid-induced protein kinase (“SGK”) is a downstream target in the PI3K/Akt pathway, believed to play a part in cancers such as breast and prostate cancer. Thus, it is desirable to identify compounds that inhibit SGK.
Ca2+/calmodulin-dependent protein kinase II (“CaMKII”) indirectly modulates Fas-mediated signalling in glioma. Therefore inhibition of CaMK II may be effective in the treatment of glioma. See, Bao Feng Yang et al., J. Biological Chemistry, 278:7043-7050 (2003). Thus, it is desirable to identify compounds that inhibit CaMKII.
Ret is a proto-oncogene implicated in many cancers such as thyroid cancer. Thus, it is desirable to identify compounds that inhibit Ret.
Endothelial-cell specific receptor protein tyrosine kinases such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas). Thus, it is desirable to identify compounds that inhibit KDR.
Ron (recepteur d'origine natais) is a receptor tyrosine kinase that is part of the MET proto-oncogene family. Inhibition of Ron has been shown to lead to a decrease in proliferation and induction of apoptosis. Thus, it is desirable to identify inhibitors of Ron.
IGF-1R (type 1 insulin-like growth factor receptor) performs important roles in cell division, development, and metabolism, and in its activated state, plays a role in oncogenesis and suppression of apoptosis. IGF-1R is known to be overexpressed in a number of cancer cell lines (IGF-1R overexpression is linked to acromegaly and to cancer of the prostate). By contrast, down-regulation of IGF-1R expression has been shown to result in the inhibition of tumorigenesis and an increased apoptosis of tumor cells. Thus, it is desirable to identify compounds that inhibit IGF-1R.
Some cancers develop resistance to certain kinase inhibitors over time and treatment. Resistance to a particular kinase inhibitor can be mediated by a loss of suppression of an enzyme at a branchpoint in the kinase pathway. The loss of suppression may lead to inappropriate activation of a parallel pathway from the original pathway. Thus, it is desirable to identify compounds that inhibit at least two kinases in order to provide compounds that are more efficacious than a very specific narrowly targeted compound that inhibits only one kinase. In particular, it is desirable to identify compounds that inhibit at least two of the Abl, Aurora-A, Blk, c-Raf, cSRC, Src, PRK2, FGFR3, Flt3, Lck, Mek1, PDK-1, GSK3β, EGFR, p70S6K, BMX, SGK, CaMKII, Tie-2, Ret, IGF-1R, Ron, and KDR kinases in animals, including humans, for the treatment and/or prevention of various diseases and conditions such as cancer.
U.S. Pat. No. 6,232,320, International Patent Publication Nos. WO 00/75145 and 99/62908 describes cell adhesion inhibiting antiinfammatory compounds. International Patent Publication No. 03/080064 describes kinase inhibitors. U.S. Pat. No. 6,713,474 describes pyrrolopyrimidines as therapeutic agents.
U.S. Pat. No. 6,541,481 describes substituted bicyclic derivatives useful as anticancer agents.
T. Peng et al., J. Chem. Inf. Comput. Sci.:43:298-303 (2003) describes 3D-QSAR and receptor modeling of tyrosine kinase inhyibitors with flexible atom receptor model (FLARM). International Patent Publication No. WO 98/43973 describes intermediate products and method for the production of pyrimidine derivatives. U.S. Pat. No. 6,610,847, International Patent Publication Nos. WO 99/65908 and WO 99/65909 describe pyrrolo[2,3-d]pyrimidine compounds. U.S. Pat. No. 6,635,762 describes monocyclic-7H-pyrrolo[2,3-d]pyrimidine compounds. International Patent Publication No. WO 02/30944 describes fluorescent nuceobase conjugates having anionic linkers. International Patent Publication No. WO 04/009600 describes 1-heterocyclyalkyl-3-sulfonylazaindole or azaindazole derivatives as 5-hydroxytryptamine-6 ligands. International Patent Publication No. WO04/007479 describes 3-guanidinocarbonyl-1-heteroaryl-indole derivatives. International Patent Publication No. WO 03/101990 describes 1-(aminoalkyl)-3-sulfonylazaindoles as 5-hydroxytryptamine-6 ligands.
International Patent Publication No. WO 02/096909 describes optical resolution of (1-benzyl-4-methylpiperidin-3-yl)-methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinase inhibitors. International Patent Publication No. WO02/50306 describes processes for determining the biological activity of epidermal growth factor receptor tyrosine kinase inhibitors. International Patent Publication No. WO02/41882 describes combination comprising an agent decreasing VEGF activity and an agent decreasing EGF activity.
International Patent Publication No. WO 03/000187 describes novel pyrazolo- and pyrrolo-pyrimidines. International Patent Publication No. WO 02/057267, U.S. Pat. Nos. 6,686,366, 6,680,324, and 6,673,802 describe compounds specific to adenosine A1, A2A, and A3 receptors. International Patent Publication No. WO 01/47507 describes combinations of a receptor tyrosine kinase inhibitor with an organic compound capable of binding to α1-acidic glycoprotein. International Patent Publication No. WO 04/013141 describes condensed pyridines and pyrimidines with TIE2 (TEK) activity. International Patent Publication No. WO 04/014850 describes substituted aminopyrimidines as neurokinin antagonists.
International Patent Publication No. WO 03/000695 describes pyrrolopyrimidines as protein kinase inhibitors. U.S. Pat. No. 6,187,778 describes 4-aminopyrrole (3,4-d) pyrimidines as neuropeptide Y receptor antagonists. U.S. Pat. Nos. 6,140,317, 6,140,332, and 6,180,636 describe pyrrolopyrimidines. U.S. Pat. Nos. 6,696,455, 6,537,999 and 5,877,178 describe pyrimidine derivatives. U.S. Pat. No. 5,958,930 describes pyrrolo pyrimidine and furo pyrimidine derivatives.
International Patent Publication No. 03/000688 describes the preparation of azaindoles as protein kinase inhibitors. International Patent Publication Nos. WO 03/018021 and WO 03/018022 describe pyrimidines for treating IGF-1R related disorders, International Patent Publication No. WO 02/092599 describes pyrrolopyrimidines for the treatment of a disease that responds to an inhibition of the IGF-1R tyrosine kinase, International Patent Publication No. WO 01/72751 describes pyrrolopyrimidines as tyrosine kinase inhibitors. International Patent Publication No. WO 00/71129 describes pyrrolotriazine inhibitors of kinases. International Patent Publication No. WO 97/28161 describes pyrrolo[2,3-d]pyrimidines and their use as tyrosine kinase inhibitors.
Although the anticancer compounds described above have made a significant contribution to the art, there is a continuing need to improve anticancer pharmaceuticals with better selectivity or potency, reduced toxicity, or fewer side effects.